We are investigating the effects of different constitutents of marihuana (cannabinoids) on male reproductive functions. Treatment of male mice with the main psychoactive cannabinoid, Delta9-tetrahydrocannabinol (THC), or with non-psychoactive cannabinoids, cannabinol (CBN) or cannabidiol (CBD), can lead to impairment of sex hormone production, sexual behavior and fertility. We have shown that THC can both increase and reduce plasma testosterone (T) levels depending on the dose and interval between drug treatment and T measurement. In order to identify the methanisms responsible for these effects, we will examine content and turnover of dopamine, noradrenalin and serotonin in several brain areas; hypothalamic levels of LHRH; cytoplasmic androgen and estrogen receptors in the hypothalamus and the pituitary; pituitary responsiveness to LHRH and testicular responsiveness to LH in adult male mice given different doses of THC. We have demonstrated that cannabinoids can inhibit testicular T production in vitro. In order to evaluate the contributions of this direct gonadal effect to changes in plasma T levels observed in vivo in cannabinoid-treated animals, we will study the consequences of oral administration of THC to hypophysectomized, hCG-treated mice and of unilateral intratesticular THC injections in intact animals. In a separate series of experiments, we will examine the effects of chronic treatment with various doses of THC, CBN and CBD on fertility of treated mice and their progeny and the reversibility of these effects. We have preliminary evidence that cannabinoids may be mutagenic. Finally, we will compare the effects of combined chronic treatment with cannabinoids and alcohol to the consequences of chronic treatment with cannabinoids alone or alcohol alone. These studies will provide new information on the mechanisms of cannabinoid action on the pituitary and the testis, on the impact of chronic exposure to these compounds on fertility and on the interaction of marihuana and alcohol. This information is needed for evaluating the risks of marihuana use in human populations.